The Human Genome Project has made it increasingly possible to study the biology of cells, and tissues at the genetic and molecular level using high-throughput technologies. The NIH Chemical Genomics Center (NCGC) was created as part of the NIH Roadmap Molecular Libraries Initiative, to establish a program in chemical genomics, defined as the use of small organic compounds to study gene products and pathways encoded by the genome. By providing capacities in the academic sector to identify bioactive compounds for targets, pathways, and cellular phenotypes, this program is bringing the power and diversity of small-molecule screening, chemistry, and informatics to broad array of researchers attempting to determine the function of the tens of thousands of human genes encoded by the genome. The NCGC, together with the extramural centers of the Molecular Libraries Screening Center Network, is exploring the majority of human and other genomes for which no small-molecule chemical probes have been identified. This initiative promises to significantly improve the understanding of mechanisms by which genes and their protein products function and accelerate the development of therapies for human diseases based on knowledge of the genome. This year has seen a dramatic increase in the NCGC's capacities, increasing staff from 4 to 19, acquiring and outfitting temporary lab space, and beginning screening and chemistry operations. Since beginning screening in May 2005, the NCGC has generated over 1.2 million data points on 10 assays, and has begun to place these HTS data into PubChem (www.pubchem.ncbi.nlm.gov), the freely available database of small molecules and their activities developed as part of the Molecular Libraries Roadmap by the National Center for Biotechnology Information.